Towards the Development of Artificial Bone Grafts: Combining Synthetic Biomineralisation with 3D Printing.

A synthetic technique inspired by the biomineralisation process in nacre has been previously reported to be effective in replicating the nanostructural elements of nacre in 2D chitosan hydrogel films. Here we evaluate the applicability of this synthetic biomineralisation technique, herein called the McGrath method, in replicating the flat tabular morphology of calcium carbonate and other nanostructural elements obtained when 2D chitosan hydrogel films were used, on a 3D porous chitosan hydrogel-based scaffold, hence developing 3D chitosan-calcium carbonate composites. Nozzle extrusion-based 3D printing technology was used to develop 3D porous scaffolds using chitosan hydrogel as the printing ink in a custom-designed 3D printer. The rheology of the printing ink and print parameters were optimised in order to fabricate 3D cylindrical structures with a cubic lattice-based internal structure. The effects of various dehydration techniques, including air-drying, critical point-drying and freeze-drying, on the structural integrity of the as-printed scaffolds from the nano to macroscale, were evaluated. The final 3D composite materials were characterised using scanning electron microscopy, X-ray diffraction and energy dispersive X-ray spectroscopy. The study has shown that McGrath method can be used to develop chitosan-calcium carbonate composites wherein the mineral and matrix are in intimate association with each other at the nanoscale. This process can be successfully integrated with 3D printing technology to develop 3D compartmentalised polymer-mineral composites.

Titanium wire implants with nanotube arrays: A study model for localized cancer treatment.

Adverse complications associated with systemic administration of anti-cancer drugs are a major problem in cancer therapy in current clinical practice. To increase effectiveness and reduce side effects, localized drug delivery to tumour sites requiring therapy is essential. Direct delivery of potent anti-cancer drugs locally to the cancer site based on nanotechnology has been recognised as a promising alternative approach. Previously, we reported the design and fabrication of nano-engineered 3D titanium wire based implants with titania (TiO2) nanotube arrays (Ti-TNTs) for applications such as bone integration by using in-vitro culture systems. The aim of present study is to demonstrate the feasibility of using such Ti-TNTs loaded with anti-cancer agent for localized cancer therapy using pre-clinical cancer models and to test local drug delivery efficiency and anti-tumour efficacy within the tumour environment. TNF-related apoptosis-inducing ligand (TRAIL) which has proven anti-cancer properties was selected as the model drug for therapeutic delivery by Ti-TNTs. Our in-vitro 2D and 3D cell culture studies demonstrated a significant decrease in breast cancer cell viability upon incubation with TRAIL loaded Ti-TNT implants (TRAIL-TNTs). Subcutaneous tumour xenografts were established to test TRAIL-TNTs implant performance in the tumour environment by monitoring the changes in tumour burden over a selected time course. TRAIL-TNTs showed a significant regression in tumour burden within the first three days of implant insertion at the tumour site. Based on current experimental findings these Ti-TNTs wire implants have shown promising capacity to load and deliver anti-cancer agents maintaining their efficacy for cancer treatment.

Non-eroding drug-releasing implants with ordered nanoporous and nanotubular structures: concepts for controlling drug release.

To address the limitations of systemic drug delivery, localized drug delivery systems (LDDS) based on nano-engineered drug-releasing implants are recognized as a promising alternative. Nanoporous anodic alumina (NAA) and nanotubular titania (TNT) fabricated by a simple, self-ordering electrochemical process, with regard to their outstanding properties, have emerged as one of the most reliable contenders for these applications. This review highlights the development of new LDDS based on NAA and TNT, focusing on a series of strategies for controlling their drug release characteristics that are based on: modification of their nanopore/nanotube structures, altering internal chemical functionalities, controlling pore openings by biopolymer coatings and using polymeric micelles as drug nano-carriers loaded within the implants. Several new strategies on externally triggered stimuli-responsive drug release for LDDS are also reviewed, and their significance toward the development of advanced smart implants for localized therapy is discussed. Finally, the review is summarized with conclusions and future prospects in this research field.

Polymeric micelles for multidrug delivery and combination therapy.

The use of conventional therapy based on a single therapeutic agent is not optimal to treat human diseases. The concept called "combination therapy", based on simultaneous administration of multiple therapeutics is recognized as a more efficient solution. Interestingly, this concept has been in use since ancient times in traditional herbal remedies with drug combinations, despite mechanisms of these therapeutics not fully comprehended by scientists. This idea has been recently re-enacted in modern scenarios with the introduction of polymeric micelles loaded with several drugs as multidrug nanocarriers. This Concept article presents current research and developments on the application of polymeric micelles for multidrug delivery and combination therapy. The principles of micelle formation, their structure, and the developments and concept of multidrug delivery are introduced, followed by discussion on recent advances of multidrug delivery concepts directed towards targeted drug delivery and cancer, gene, and RNA therapies. The advantages of various polymeric micelles designed for different applications, and new developments combined with diagnostics and imaging are elucidated. A compilation work from our group based on multidrug-loaded micelles as carriers in drug-releasing implants for local delivery systems based on titania nanotubes is summarized. Finally, an overview of recent developments and prospective outlook for future trends in this field is given.